Traumatic injury is a major pediatric public health concern. Annually, over 8 million children under the age of 17 years sustain some physical injury and nearly half a million children sustain traumatic injury to the brain (TBI). Traumatic stress (TS) from a variety of etiologies, including traumatic injury, has been linked to myriad changes in the neurobiological stress response systems and to brain structure and function. TBI and TS have overlapping symptoms, may alter the structure and function of similar core brain regions, and activate endocrine stress response systems. Our preliminary studies suggested significant dysregulation of multiple stress systems in youth with either TBI or extracranial injury that persisted years after injury. Despite the high occurrence and co-occurrence of TBI and TS following pediatric injury, little is known about post-traumatic changes in stress-responsive systems. Using a longitudinal, prospective cohort design, we will examine post- traumatic changes to stress systems during the first year following traumatic injury in children and adolescents ages 8-15 who are hospitalized following significant traumatic brain and/or extracranial injuries sustained in motor vehicle collisions. We will examine biomarkers from each stress system as follows: the hypothalamic- pituitary-adrenal axis, salivary cortisol;the noradrenergic system, salivary 1-amylase, heart rate, and heart rate variability;and prefrontal-limbic circuitry, measures of volume or integrity of gray matter nuclei, prefrontal cortex, and related pathways. Aim 1 investigates the impact of traumatic injury on the biomarkers of the three stress-responsive neurobiological systems during the first year after TBI or extracranial injury. Aim 2 examines the degree to which biomarkers of these stress-responsive systems mediate the relation of injury characteristics to longitudinal cognitive, neurobehavioral, and psychological health outcomes affected by TBI and/or TS. This interdisciplinary and longitudinal approach to the study of traumatic injury examines the joint influences of changes in multiple stress-response systems and the brain on key outcomes that are common to TBI and TS populations. These outcomes include reduced attentional efficiency, memory dysfunction, inhibitory dyscontrol, somatic complaints, hyperarousal, anxiety, and depression. This novel program of research has the potential to advance both scientific inquiry and clinical care of pediatric injury patients. Better understanding of the neurobiological mechanisms contributing to chronic morbidity following traumatic injuries is essential to design targeted interventions to reduce morbidity and enhance recovery. PUBLIC HEALTH RELEVANCE: Chronic activation of stress response systems following injury to the brain or other body region is a major public health concern. Activation of these systems contributes to poor physical and psychological health outcomes, including internalizing disorders, immune dysfunction, hypertension, and insulin resistance. Understanding relations between neurobiological and psychological responses following pediatric injury will guide development of targeted strategies to improve health related quality of life.